Lamotrigine in Pregnancy – Is Lamotrigine Safe in Pregnancy?
Time to read: 4 minutes
Lamotrigine is a synthetic phenyltriazine drug with analgesic and antiepileptic properties. It is primarily used as an anticonvulsant for the adjunctive treatment of seizures in epilepsy. Lamotrigine, in psychiatry, is used in the treatment of bipolar disorder.
Lamotrigine has multiple mechanisms of action, which give this drug its diverse anti-seizure properties as well as its novel thymoleptic and psychotropic properties.
Research shows that lamotrigine’s clinical profile is the result of distinct and overlapping mechanisms that contribute to each of its pharmacological actions. [Ketter T et al., 2003]
Central to its anti-seizure activity is its action on neuronal ion channels, particularly sodium channels and chloride channels. Proconvulsant activity is linked to Na+ influx through voltage-gated Na+ channels, which inturn leads to glutamate excitotoxicity.
Lamotrigine blocks voltage-gated Na+ channels inhibiting glutamate excitotoxicity.
Lamotrigine also enhances the release of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter that attenuates neuronal electrical activity associated with paroxysms.
Lamotrigine is approved for the management of bipolar I disorder due to its stabilising effect on depressive symptoms. Lamotrigine is evidence-based in the treatment of acute depressive episodes and prophylaxis of depressive episodes as part of Bipolar I disorder. Lamotrigine also seems to have good efficacy for Bipolar II depression. Read more about mood stabilisers in the treatment of bipolar disorder.
Administration of lamotrigine is purported to have anti-glutamatergic effects as well as putative anti-kindling effects. Kindling is described as the clinical development of bipolar disorder from reactive and triggered symptoms to a more frequent, severe and spontaneously occurring form.
Although lamotrigine is commonly prescribed and has a good safety profile, a study in 2008 in the Neurology journal reported that lamotrigine exposure increased the frequency of congenital anomalies such as cleft palate in babies [Holmes L et al., 2008]. As such, the US Food and Drug Administration now includes a mandatory warning on this specific risk in patient information included with this drug.
To further test this, a new study by Dolk and colleagues aimed to determine the discrepancies in the literature by investigating the association between orofacial clefts and lamotrigine exposure during pregnancy. [Dolk H et al., 2016]
WHO AND WHAT WAS STUDIED?
This was a population-based case malformed-control study of 10.1 million births between 1995 and 2011 across 16 countries in Europe.
Researchers investigated the relative risk of orofacial cleft and clubfoot malformations after lamotrigine monotherapy in the first-trimester.
WHAT WERE THE FINDINGS?
In the study population, there were 226,806 births with a major congenital malformation, of which 88% were non-chromosomal, and 12% were chromosomal related. Of the non-chromosomal congenital anomalies cases, 1,286 babies had been exposed to an antiepileptic drug during the first trimester.
Of these, 147 were lamotrigine monotherapy-exposed babies, and another 98 had been exposed to lamotrigine as part of a polytherapy strategy with valproic acid. Furthermore, in 77.1% of cases, the reason for lamotrigine prescription was for maternal epilepsy.
The results of this study showed that orofacial cleft was significantly associated with exposure to antiepileptic drugs.
However, for lamotrigine monotherapy, there was no report of a significant association with an orofacial cleft or cleft palate. From this data, the researchers report that the risk of developing an orofacial cleft from lamotrigine is less than 1 in 550 lamotrigine-exposed babies.
The data on the presence of clubfoot after exposure to lamotrigine in the first trimester was non-existent. The authors found no strong independent evidence of a risk of clubfoot subsequent to their original signal. There was no association between clubfoot and any antiepileptic drug taken during the first trimester of pregnancy.
We could not find statistically significant independent evidence of a clubfoot excess. However, the overall excess including the original signal remains statistically significant. We recommend that cohort studies also keep this anomaly under review using comparable diagnostic inclusion criteria.
WHAT DOES THE STUDY TELL US?
This study shows that, in contrast to the Neurology report in 2008, there is no increased risk of orofacial cleft or clubfoot if the mother was being administered lamotrigine during the first trimester.
STRENGTH AND LIMITATIONS
This study has a large population size and is well controlled for in comparison to many other anti-epileptic drug cohort studies.
However, this study does not include a range of lamotrigine doses, and so it is unknown whether larger doses are associated with the risk of congenital anomalies.
Case-control studies can be prone to over or underestimation of the odds ratios depending on the risk of the control exposure.
Finally, this study was, in part, funded and sponsored by GlaxoSmithKline, who was involved in the planning stage of this study. GlaxoSmithKline produces and sells the product, Lamictal, a lamotrigine product.
THE BIG PICTURE
This report is a follow-up study by the same working group that looked to determine whether lamotrigine increased the relative risk of orofacial cleft [Dolk H et al., 2008]. That original study analysed 3.8 million births and had shown there was no evidence linking lamotrigine monotherapy with orofacial cleft malformation.
This new study is more than double the size of the previous study and also looks at the risk of other congenital anomalies such as clubfoot. This is because their previous study originally found evidence of a significant presence of clubfoot after lamotrigine monotherapy during the first trimester of pregnancy. The current study shows no statistically significant independent evidence of a clubfoot excess.
Many anti-epileptic drugs, such as topiramate, have been previously associated with orofacial clefts. However, it is unknown what the underlying biological mechanism that could connect anti-epileptic drugs and congenital anomalies. Some genetically determined individual susceptibility may also contribute. [Tomson T et al., 2015]
The risk of major congenital malformations is highest with Valproate compared to other anti-epileptics.
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